A critical role for the paraventricular nucleus of the hypothalamus in the regulation of the volume reflex in normal and various cardiovascular disease states

Abstract

Purpose of review

This review focuses on studies implicating forebrain neural pathways and neuromodulator systems, particularly the nitric oxide system within the paraventricular nucleus of the hypothalamus in regulating neurohumoral drive, autonomic pathways and fluid balance.

Recent findings

Accumulating evidence from animals with experimental models of hypertension and heart failure as well as humans with hypertension suggests that alterations in central neural pathways, particularly within the PVN neuromodulated by neuronal nitric oxide are involved in regulating sympathetic outflow particularly to the kidney resulting in alterations in fluid balance commonly observed in hypertension and heart failure states.

Summary

The characteristics of the hypertensive and heart failure states include alterations in neuronal nitric oxide within the PVN to cause an increase in renal sympathetic nerve activity to result in sodium and fluid retention in these diseases. A comprehensive understanding of these mechanisms will enhance our ability to treat hypertensive and heart failure conditions and their cardiovascular complications more efficiently.

Introduction

Accumulating evidence from animals with experimental models of hypertension and heart failure, and humans with hypertension suggest that alterations in central neural pathways, neurotransmitters and neuromodulators involved in regulating sympathetic outflow may be important in the alterations in neurohumoral drive, autonomic reflexes and fluid balance commonly observed in hypertension and heart failure. The paraventricular nucleus of the hypothalamus (PVN) is an important site for the integration and dictating a concerted response in terms of a variety of neural and humoral signals regulating sympathetic drive and normal fluid volume status [1, 2]. The PVN includes neuroendocrine-related functional neurons that project to the median eminence, posterior pituitary, and pre-autonomic neurons that send long descending projections to the brain stem and spinal cord regions that are important in dictating autonomic outflow and fluid balance [3–5]. Many PVN neurons project to the rostral ventrolateral medulla (RVLM), which have been shown to correlate with activation of renal sympathetic nerve activity (RSNA) involved in sodium and water regulation by the kidney [6].

This review highlights and describes the studies that examine and implicate forebrain neural pathways and neuromodulator systems, particularly the nitric oxide (NO) system within the PVN in regulating neurohumoral drive, autonomic pathways and fluid balance. It discusses a homeostatic role for NO mechanisms within the PVN involved in the normal volume reflex arc in general and dysfunction in two disease states, hypertension and heart failure known to demonstrate avid sodium retention.

The normal volume reflex

Classically an increase in blood volume is sensed by stretch receptors located in the great veins and the left atria. This information is transmitted to the central nervous system (CNS) via the vagus nerve with its primary first synapse in the nucleus tractus solitarius (NTS) in the brain stem. Challenges in volume, such as the change in circulating blood volume, the changes in atrial and ventricular filling pressures, on the low-pressure side of the circulation evoke reflex responses to regulate water and sodium excretion/retention by the kidney [7, 8]. For example, a decrease in circulating volume, such as that observed during an acute hemorrhage, induces a reflex increase in RSNA [9, 10] and the secretion of arginine vasopressin [9, 11, 12], resulting in an increase in the reabsorption of sodium and water in the kidney and a decrease in urine production. This homeostatic volume reflex response prevents a decrease in body fluids to maintain overall blood pressure in the normal range. Alternatively, when the circulating volume is increased, such as in experimentally induced volume expansion (VE), this elicits an opposite response, that induces a decrease in RSNA and vasopressin secretion, resulting in an increase in sodium and water excretion [13–15]. Sympathetic innervation to the kidney elicits three important effects, first, it regulates renal blood flow by dictating renal vasoconstriction, second, it causes renin release, and third, it causes direct sodium and water reabsorption in the renal tubular cells [16, 17]. Thus, these reflex changes in RSNA to acute VE play a vital role in the efferent limb of the volume reflex to cause diuresis and natriuresis [18] as depicted by Figure 1.

Figure 1:

A and B: Urine flow and sodium excretion in response to acute volume expansion (VE) (% of body weight) with isotonic saline. * P<0.05 compared with the intact group. C and D: Renal sympathetic nerve activity (RSNA, as % of basal activity) in response to acute VE (% of body weight and change in central venous pressure) with isotonic saline in normal rats (n=6).

The volume status in the body is then relayed from the NTS in the brainstem to the higher hypothalamic structures/areas where it is processed and integrated resulting in a widespread neurohumoral response. One particular part of the hypothalamus that features prominently in this reflex is the PVN. The PVN has been well known as an important integrating site in the forebrain for regulating sympathetic nerve activity [5, 2]. This, combined with the known role of the PVN in fluid balance and vasopressin release, puts the PVN in a unique position of regulating “sodium excretion” via renal nerves and “water excretion” via vasopressin release at rest and during volume challenges. Other studies, including our own, suggest that PVN neurons are involved in mediating the neural component of cardiovascular reflexes by influencing RSNA [19, 20]. Electrophysiological evidence shows that VE activates neurons within the PVN, showing that the PVN is involved in the normal volume reflex response [21].

The role of the paraventricular nucleus in the normal volume reflex

The PVN is well known to be involved in the control of fluid balance. However, most of the studies examining this nucleus have emphasized the magnocellular neurons, which are involved in the humoral control of fluid balance by the action of antidiuretic hormone, vasopressin which increases the permeability of collecting tubules to water leading to water retention. It is well established that the magnocellular neurons in the PVN and the supraoptic nuclei are responsible for the humoral component of regulating fluid balance [22]; however, neurons within specific portions of the PVN (dorsal cap and ventromedial PVN) are known to be involved in the control of central autonomic outflow to various peripheral organs including the kidneys. Further, the PVN is the most rostral brain structure that directly contributes to the control of the overall sympathetic outflow and RSNA in particular, since it projects to the intermediolateral cell column of the spinal cord that provides innervation to the heart and the kidneys, specifically [23, 24]. The parvocellular neurons in the PVN that dictate sodium reabsorption by their actions on renal nerves, known to regulate sodium reabsorption in the kidneys, are next to the magnocellular neurons that dictate water reabsorption. This arrangement is ideal for the control and regulation of overall extracellular fluid volume and ultimately blood volume in the body. Further, the PVN is anatomically and functionally connected to neurons residing in the forebrain sensory circumventricular organs; parts of the brain lacking functional blood-brain-barrier and known for their ability to sense slight/minor changes in sodium concentration/osmolality being located lateral to the third ventricle [25]. This is additional evidence that the PVN is a critical site for coordination and integration of neurogenic and hormonal actions on the cardiovascular system and the kidney in response to changes in blood volume (volume reflex) as well as sodium concentration/osmolality in the body.

These several lines of evidence provide the credence for a critical role for the parvocellular neurons of the PVN in the neural regulation of fluid balance [2]. Acute VE produces a decrease in RSNA in monkeys, dogs, sheep, rabbits, cats and rats [26–30]. Spinal cord projecting PVN neurons respond to acute VE [31]. Chemical stimulation of cell bodies within the PVN elicits a reduction in RSNA [32–34], similar to that observed during VE [16]. We have shown that selective destruction of parvocellular neurons in the PVN with kainic acid, known to destroy cell bodies but not fibers-of-passage [35] significantly attenuates the reflex reduction of RSNA observed in response to acute isotonic VE [36]. This evidence suggests that it is likely that the parvocellular neurons within the PVN are a critical relay in the reflex arc that is activated during acute VE.

There is also ample evidence from many studies that the sympathetic nervous system plays a major role in determining the pressor response to central hypertonicity [37] [38]. Previously, it has been demonstrated that the PVN contributes to the cardiovascular and renal responses to increased cerebrospinal fluid sodium concentration [39, 26]. These investigations have shown that inhibition of neural activity within the PVN abolishes the increase in arterial pressure and central venous pressure, inhibits the increased urinary sodium excretion and glomerular filtration rate, and reversed the reduction in RSNA induced by intracerebroventricular hypertonic sodium chloride. Further, physiologically induced hypertonicity, by dehydration results in higher renal and lumbar sympathetic output originating from the PVN in anesthetized rats [40–42]. This evidence supports the hypothesis that the PVN is a critical regulatory/integrative structure in sodium-induced alterations in cardiovascular and renal function mediated by the brain.

The role of nitric oxide within the PVN in the normal volume reflex

The specific details of the pathways within the CNS and the specific neurotransmitter substances involved in the volume reflex arc have been investigated to some extent. There is growing evidence that NO acts as a non-synaptic gaseous neurotransmitter to affect synaptic function in the CNS [43, 44]. In the hypothalamus, neuronal NO synthase (nNOS)-positive neurons are found primarily in the PVN and supraoptic nucleus [43, 45, 46]. As an atypical gaseous neuromodulator, NO elicits multiple effects on the CNS regulating presynaptic neurotransmitter transport and release and postsynaptic receptor activity [43, 47, 48]. nNOS has been shown to play an important role in regulating sympathetic nerve activity [49, 50]. The studies from our and other laboratories have shown that the administration of an NO donor, sodium nitroprusside into the PVN produces a decrease in RSNA, blood pressure, and heart rate in rats [51, 52, 46]. Conversely, administration of a NOS blocker [N^G- monomethyl-L-arginine (L-NMMA)] or N5-(1-Iminoethyl)-L-ornithine (L-NIO) into the PVN increases RSNA, blood pressure, and heart rate [52, 53]. This suggests that there is a tonic NO-mediated inhibition of parvocellular neurons within the PVN that mediate renal sympathetic outflow. NO elicits a so-called “breaking effect” to reduce neuronal activity elucidated by activation of glutamatergic NMDA receptors to prevent over-excitation [54]. The inhibitory effects of NO are also mediated by the release of GABA [55, 56].

We also have observed that acute VE induces a graded increase in central venous pressure with a concomitant associated diuresis and natriuresis (Figure 1). The diuretic and natriuretic responses are blunted by the blockade of NO within the PVN [57]. The effects are mediated via the renal sympathetic nerves since renal denervation abolished the attenuated diuresis and natriuresis to blockade of NO within the PVN. Further, direct measurement of renal sympatho-inhibition induced by VE is significantly blunted after the central administration of an NO blocker within the PVN. Consistent with these observations acute VE induces an increase in NOx in the perfusate of the PVN. These studies taken together show that NO within the PVN is involved in renal sympatho-inhibition during acute VE [57]. In rats with a normal volume status (without VE), administration of L-NMMA into the PVN does not induce significant changes in urine flow or sodium excretion, suggesting that blockade of NO within the PVN does not elicit significant effects on renal excretory functions under normal tonic homeostatic volume status. Previously we have observed that blockade of NO within the PVN induces an increase in RSNA, blood pressure, and heart rate [58], but this does not translate into any significant change in urine flow or sodium excretion under acute conditions. Perhaps the increase in blood pressure invokes pressure diuresis and natriuresis that counteracts the effects of the increase in RSNA that would be expected to result in sodium retention. Thus, the net effect of these opposing actions results in no change in urine flow or sodium excretion. However, during acute VE a significant increase in NO within the PVN exerts a predominant inhibition of renal sympathetic outflow that results in increased diuresis and natriuresis. Consistent with these observations blockade of NO within the PVN induced a marked attenuation of the decrease in RSNA and a significantly blunted increase in urine production and sodium excretion caused by acute VE.

The detailed mechanisms of how the peripheral acute VE can induce NO synthesis in the PVN remains to be addressed. It has been reported that the major sensors of a volume challenge are the cardiopulmonary mechanical receptors, which are primarily on the cardiac atrium and ventricle [13]. Stimulation of these receptors via increasing atrial pressure by volume loading induces the activation of neurons in the NTS and the inhibition of RSNA [13]. The anatomic evidence has shown that there is a direct projection from the NTS to the hypothalamus and other forebrain regions [59]. Consistent with these observations, acute VE causes excitation of most paraventriculo-spinal neurons in the PVN [31]. Renal sympatho-inhibitory responses [19] as well renal vasodilatory responses [60] to acute volume load are attenuated after lesions of parvocellular neurons in the PVN. These parvocellular neurons in the PVN contain nNOS. Thus, it is conceivable that this is a pathway for the stimulation of NO synthesis in the PVN. However, more direct evidence on the afferent arc of this volume reflex that induces the increase in NO synthesis remains to be established as well as the involvement of GABA within the PVN. Our studies show that nNOS in parvocellular neurons within the PVN contributes to renal nerve-mediated changes in diuresis and natriuresis to acute VE and thus plays an important role in the regulation of the volume reflex in normal rats.

Alterations of NO mechanisms within the PVN involved in the blunted volume reflex in Hypertension and Heart Failure

The normal volume reflex discussed above plays an important role in balancing body fluid metabolism and stabilizing arterial pressure over a long-term basis. The impairment of this volume reflex is believed to contribute to cardiovascular complications and aggravation of some disease states, including hypertension, and heart failure [7, 61–63]. Our and other studies have revealed that the normal volume reflex is impaired and/or blunted in various disease conditions, including hypertension [61], chronic heart failure (CHF) [17], and diabetes [18]. This blunted volume reflex results in water and sodium retention leading to overloading of fluid in these disease states, which is a major factor in the development and further aggravation of these disease conditions. An altered NO system in the hypothalamus or the PVN has been demonstrated in both hypertension [64, 65] and CHF [62, 63]. The proceeding section will detail the evidence for the deficiency of NO mechanisms in the PVN which may be the major cause of the blunted volume reflex observed in hypertensive and heart failure conditions.

Hypertension

Fifty million Americans have elevated blood pressure and/or are taking anti-hypertensive medications. Hypertension represents a significant risk factor for cardiovascular and renal disorders and general end-organ damage throughout the body [66, 67]. Thus, investigations into the fundamental underlying mechanisms involved in regulating fluid balance and thus long-term arterial pressure regulation are being vigorously investigated.

The spontaneously hypertensive rat (SHR) is a leading animal model for human essential hypertension [68]. It develops an increase in resting arterial pressure with a concomitant widespread increase in sympathetic nerve activity to various organs, particularly to the kidney [69]. Renal denervation delays hypertension in young SHR [70–73]. Blockade of the autonomic ganglia reduces resting arterial pressure more in SHR than their genetic controls, the Wistar-Kyoto (WKY) rats [69]. Transection caudal to the hypothalamus reduces the elevated arterial pressure in the SHR but not the WKY rat [74] suggesting a supra-medullar source for the neurogenic activation in SHR. Further, ablation of the PVN also reduces arterial pressure in the SHR [75]. These results suggest a neurogenic etiology for hypertension in the SHR and identify the PVN as a potential target region for the genesis of sympathetic drive in the hypertensive state [76, 77]. In addition, there is interesting evidence that a deficit in the inhibitory neurotransmitter, GABA, in the hypothalamus may contribute to the sympatho-excitation leading to the hypertensive state in the SHR [78, 79]. It is of interest to note that NO has its inhibitory effect via the release of GABA as discussed above [55, 56]. Consistent with this, it is reported that levels of GABA and GABA turnover rates are reduced in the hypothalamus of SHR [78, 80]. In addition, direct activation of GABA receptors by microinjections of GABA agonists into the PVN lowers arterial pressure more in the SHR than in the WKY rats [81, 82].

Previously we have shown that NO has an inhibitory effect on arterial pressure and sympathetic nerve activity via the release of GABA [52]. Electrophysiological experiments on the PVN slices have shown that NO inhibits pre-autonomic neurons in the PVN via the release of GABA [56, 55]. NO, as well as GABA [83], participate in regulating the cardiovascular system via a central inhibitory effect on the sympathetic nervous system. However, whether a deficit in the NO system is associated with hypertension in the SHR is not identified. Our previous study has documented that there is a decrease in the number of NOS-positive cells in the PVN of SHR compared with the WKY rat (Figure 2). The decreased number of NOS positive cells in the PVN of hypertensive rats may contribute to the sympatho-excitatory state in the SHR.

Figure 2:

Photomicrographs presents NADPH-diaphorase labeled neurons in the PVN of the Wistar-Kyoto (WKY) and spontaneously hypertensive rat (SHR). The PVN is clearly outlined with cells of medium to large size neurons concentrated in the ventral and lateral portion of the PVN.

The sensitivity of the volume reflex is impaired in the SHR rat and other models of hypertension. We have previously shown that there is a greater diuresis and natriuresis in the young SHR due to slightly increased renal perfusion pressure, and the renal nerves produce greater retention of water and sodium in SHR compared to WKY [61]. These results suggest that there is an inadequate renal sympatho-inhibition in the SHR compared to the WKY, indicative of a blunted volume reflex in the young SHR. Consistent with these observations Huang and Leenen have shown that acute VE produces an attenuated renal sympatho-inhibitory response in young SHR on a high-salt diet compared to WKY on a similar sodium diet [84]. Thornton et al. have shown that there is complete abolition of lumbar sympathetic inhibition to acute VE in salt-sensitive SHR [85]. Acute VE produces a blunted renal sympatho-inhibitory response in SHR as compared to WKY rats in 16-week-old rats [86], impairs arterial baroreceptor reflex and cardiopulmonary vagal reflex in conscious SHR [87].

To examine the role of NO mechanisms in the PVN and its role in another model of hypertension, we have performed a series of experiments to determine the contribution of NO in the PVN during the development of hypertension in one-kidney renal wrap hypertensive rats. The renal wrap model of hypertension is a salt-sensitive, nongenetically mediated experimental model of hypertension that has been long used to evaluate neurohormonal changes in hypertension [88–90]. We examine whether a reduction in the activity of the NO system within the PVN is involved in the development and maintenance of hypertension. In this study, there is a decrease in nNOS in the PVN during the onset of hypertension (Figure 3). Further, during both the onset and sustained phases of renal wrap hypertension, reduced PVN NO activity contributes to the elevations in blood pressure [91]. This is evidenced by a blunted elevation in blood pressure in response to L-NAME injections during both phases of renal wrap hypertension. When NO is reintroduced into the PVN, via adenoviral eNOS targeting the PVN, the overexpression of eNOS leads to significantly blunted renal wrap-mediated increases in blood pressure throughout the progression of the disease. Adenoviral eNOS did not affect the blood pressure or heart rate in sham-operated control animals, indicating the changes in NO are critical for the development of hypertension. These observations support the importance of the NO system in keeping blood pressure at normotensive levels.

Figure 3:

Photomicrographs presents NADPH-diaphorase labeled neurons in the PVN of the Control and renal wrap hypertensive rats.

These observations are consistent with observations in other models of hypertension as well [51, 92, 93]. Work by Rossi et al. showed that inhibition of NOS with a dominant-negative nNOS virus localized to the PVN further elevates mean arterial pressure in two-kidney, one-clip hypertension [94]. Their findings show that chronic interference of nNOS reduces total NO and further increases blood pressure by modulation of sympatho-excitation. The reduced functional contribution of the NOS system in these cardiovascular models may result from the changes in factors that can modulate the expression of NOS or its activity, such as superoxide, changes in cofactor activity, neuroinflammatory factors or other undetermined mechanisms. Interestingly, in two chronic models of hypertensive rats, central mineralocorticoid-induced hypertension and chronic renal failure, a significant decrease in the amount of nNOS mRNA is found in the hypothalamus and rostral and caudal ventrolateral medulla [95, 96]. Additional examination of the underlying mechanisms and their related changes in these various models of hypertension remains to be elucidated.

Interestingly endurance exercise training has been suggested to be a safe therapeutic approach for lowering arterial pressure and sympathetic activity in hypertensive individuals. Exercise training attenuates the developmental rise in resting arterial pressure [66, 80] and reduces sympathetic activity in the SHR [97, 66]. We postulates that these effects of exercise training may be due, in part, to an upregulation of the NO inhibitory mechanisms within the hypothalamus [98, 80]. This is suggested because blockade of GABA synthesis in the hypothalamus increases arterial pressure in exercise-trained but not in sedentary control SHR [98]. It was unknown, however, if exercise training up-regulates the NO system in the SHR. Daily exercise increased the number of NOS-positive cells in the PVN of the SHR to levels observed in the WKY rats [99]. These data suggest that the sympatho-inhibition associated with daily exercise in the SHR [97, 100], may be due, in part, to the increased number of NOS positive cells in the PVN.

In conclusion, altered NO mechanisms in the PVN are potentially critically involved in the altered volume reflex and lead to sodium retention and result in hypertension. It is postulated that NO mechanism dysregulation contributes to a role throughout the development and maintenance of the hypertensive process. Reduced nNOS in pre-autonomic sympathetic neurons in the PVN may influence the NO-induced changes in renal nerve activity and thus cause sodium retention which contributes to the hypertensive process. Further studies will help to understand the cellular and molecular mechanisms affecting nNOS expression, activity, and regulation in the PVN in the pathophysiological states affecting renal nerve activation and thus eventual hypertension.

Heart Failure

A pathophysiological hallmark of CHF is chronic sympatho-excitation with avid sodium retention. Several studies in patients with CHF have shown that the magnitude of this symptho-excitation and sodium retention is adversely related to the prognosis of CHF [101]. Although the precise mechanisms responsible for these alterations are not entirely clear, impaired volume reflex and resulting neurohumoral activation may contribute to this poor prognosis in CHF. We and others have previously shown that there is attenuated decrease in RSNA to acute VE in rats with CHF [102, 103]. Consistent with this observation renal denervation produces a greater diuresis and natriuresis after renal denervation in rats with heart failure [104, 105] (Figures 4A–4C). Consistent with the concept of nNOS within the PVN playing a critical role in the volume reflex, our previous data shows that the nNOS mRNA is substantially decreased in animals with experimental CHF at various central sites, including the PVN [106, 107]. NADPH-diaphorase staining shows a decrease in nNOS-positive neurons in the PVN of rats with CHF [108] (Figure 4D), suggesting a decreased activity of this enzyme-producing NO. Consistent with these observations the protein levels of nNOS within the PVN are also reduced in rats with CHF [109].

Figure 4:

A and B: Line plots showing the changes in urine flow rates and sodium excretion in anesthetized Sham and heart failure (HF) rats undergoing VE. C. Line plots showing the changes in RSNA of anesthetized Sham and HF rats undergoing VE. D. Photomicrographs presents NADPH-diaphorase labeled neurons in the PVN of Sham and HF rats. * P<0.05 compared with Sham group.

Several laboratories have investigated the role of NO within the PVN. The NO donor sodium nitroprusside has been shown to decrease blood pressure [51], RSNA, and heart rate [58], whereas blockade of NOS produced an increase in blood pressure, RSNA, and heart rate [58]. A study that evaluated the firing activity of electrophysiologically identified RVLM-projecting PVN neurons shows that the application of an NO donor inhibits the firing activity of these neurons [55]. These studies suggest that NO plays a sympatho-inhibitory role in the PVN. We have shown that the NO-mediated inhibition of RSNA is blunted in rats with CHF, which is consistent with the decrease in nNOS expression in CHF [62]. Further, antisense oligodeoxynucleotide (ODN) technology was used to prevent the translation of nNOS messenger RNA to nNOS protein within the PVN of normal control rats. The results indicate that nNOS antisense ODN evokes a sympatho-excitatory response when administered into the PVN. However, the excitatory effect of unilateral administration of nNOS antisense ODN within the PVN is blunted in rats with CHF [110]. This is consistent with a decrease in functional nNOS protein in the PVN of rats with CHF. It is also consistent with a decrease in responsiveness to NO in CHF [62]. Because the pressor responses to L-NMMA and nNOS antisense are similar in these experiments, we cannot rule out a contribution from endothelial NOS-derived NO in the response to L-NMMA. However, several studies suggest that nNOS expression is modulated by many physiological and pathological stimuli, such as neuronal injury and synaptic plasticity [111, 112]. Many of these processes are Ca²⁺ dependent. Sasaki et al. have shown that nNOS transcription is regulated by Ca²⁺ influx through a cAMP response element-binding protein family transcription factor-dependent mechanism [113]. Because NOS catalytic activity is also Ca²⁺ dependent, many substances, such as endothelin [114], angiotensin II [115], and glutamate [116], may modulate NOS activity and expression in response to increases in intracellular Ca²⁺. A change in the concentration of these substances in CHF might contribute to a reduction of nNOS synthesis and/or activity [55, 62].

In conclusion, taking all the data presented here we suggest that reduced nNOS within the PVN leads to a blunted renal sympatho-inhibition to acute VE in rats with CHF. Further, this results in a blunted diuretic and natriuretic response to acute VE in rats with CHF. It should be noted that exercise training for four weeks improved the levels of nNOS within the PVN with concomitant improvement in the renal sympatho-inhibition and diuretic and natriuretic responses to acute volume in rats with CHF [117, 118, 102]. We postulate these findings demonstrates that a loss of nNOS in the pre-autonomic PVN neurons results in a blunted volume reflex in rats with CHF. These data provide further evidence for the importance of central NO mechanisms within the PVN in the neurohumoral balance and consequent fluid balance abnormalities commonly observed in CHF.

Conclusions

This review provides compelling evidence for a critical functional role for nNOS within the PVN in the normal volume reflex. An increase in volume sensed by the volume receptors in the heart and great vessels is transmitted to the PVN to elicit release of NO which inhibits pre-autonomic neurons either directly or via GABA mechanism. The consequent renal sympatho-inhibition translates into an increase in sodium excretion and urine flow (Figure 5). Furthermore, hypertension and heart failure conditions elicit a decrease in nNOS within the PVN leading to reduced inhibition of pre-autonomic sympathetic outflow from the PVN. This leads to increased RSNA causing an increase in renin release, renal vasoconstriction and sodium retention. Future examination of the contributing factors to regulating these NO mechanisms within the PVN is expected to provide potential therapeutic targets and modalities for treatment.

Figure 5:

Schematic graph shows the neural pathways and the nitric oxide (NO) system within the PVN in regulating RSNA and fluid balance. NO mechanism within the PVN is involved in the volume reflex arc in general and dysfunction in two disease states leading to sodium retention in hypertension and heart failure. (Templates used from BioRender.com)